A novel strain-specific neutralizing epitope on glycoprotein H of Human Cytomegalovirus

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes severe clinical disease in immunosuppressed patients and congenitally infected newborn infants. Viral envelope glycoproteins represent attractive targets for vaccination or passive immunotherapy. To extend the knowledge of mechanisms of virus neutralization, monoclonal antibodies (MAbs) were generated following immunization of mice with HCMV virions. Hybridoma supernatants were screened for in vitro neutralization activity, yielding three potent MAbs 6E3, 3C11, and 2B10. MAbs 6E3 and 3C11 blocked infection of all viral strains that were tested, while MAb 2B10 neutralized only 50% of the analyzed HCMV strains. Characterization of the MAbs using indirect immunofluorescence analyses demonstrated their reactivity with recombinant derived gH. While MAbs 6E3 and 3C11 reacted with gH when expressed alone, 2B10 detected gH only when coexpressed with gB and gL. Recognition of gH by 3C11 was dependent on expression of the entire ectodomain of gH, whereas 6E3 required residues 1-629 of gH. The strain-specific determinant for neutralization by Mab 2B10 was identified as a single Met->Ile amino acid polymorphism within gH, located within the central part of the protein. The polymorphism is equally distributed among described HCMV strains. The 2B10 epitope thus represents a novel strain-specific antibody target site on gH of HCMV. The dependence of the reactivity of 2B10 for the simultaneous presence of gB/gH/gL will be of value in the structural definition of this tripartite complex. The 2B10 epitope may also represent a valuable tool for diagnostics to monitor infections/reinfections with different HCMV-strains during pregnancy or after transplantation. Importance HCMV infections are life-threatening to people with compromised or immature immune systems. Understanding the antiviral antibody repertoire induced during HCMV-infection is a necessary prerequisite to define protective antibody responses. Here, we report three novel anti-gH MAbs that potently neutralized HCMV infectivity. One of these MAbs (2B10) targets a novel strain-specific conformational epitope on gH, which only becomes accessible upon coexpression of the minimal fusion machinery gB/gH/gL. Strain-specificity is dependend on a single amino acid polymorphism within gH. Our data highlight the importance of strain-specific neutralizing antibody responses against HCMV. The 2B10 epitope may also represent a valuable tool for diagnostics to monitor infections/reinfections with different HCMV-strains during pregnancy or after transplantation. In addition, the dependence of the reactivity of 2B10 for the simultaneous presence of gB/gH/gL will be of value in the structural definition of this tripartite complex.

A TonB-Like Protein, SjdR, Is Involved in the Structural Definition of the Intercellular Septa in the Heterocyst-Forming Cyanobacterium Anabaena

Multicellularity in bacteria confers an improved adaptive capacity to environmental conditions and stresses. This includes an enhanced capability of resource utilization through a distribution of biochemical processes between constituent cells.

National policy councils for science, technology, and innovation: A scheme for structural definition and implementation

National policy councils for science, technology, and innovation have become a common institutional arrangement in supporting governments to overcome the problems of coordination derived from the complexity of national innovation systems. These organizations are expected to involve stakeholders with strategic capacity in defining long-term goals for science, technology, and innovation, to coordinate efforts and to monitor execution. However, governments face several options to devise the proper council for their purposes, and the absence of a common framework may induce theoretical and analytical difficulties. This exploratory and descriptive study proposes a scheme for defining the structure of such a council and a comprehensive approach that is based on the novel Organisation for Economic Co-operation and Development (OECD) database; analyzing the results obtained for thirty-one countries. The results obtained from the index confirm heterogeneity, while the clustering suggests three types of councils. The proposed scheme provides a standard tool for the study and implementation of these councils.

What are Implicit Definitions?

The paper surveys different notions of implicit definition. In particular, we offer an examination of a kind of definition commonly used in formal axiomatics, which in general terms is understood as providing a definition of the primitive terminology of an axiomatic theory. We argue that such “structural definitions” can be semantically understood in two different ways, namely (1) as specifications of the meaning of the primitive terms of a theory and (2) as definitions of higher-order mathematical concepts or structures. We analyze these two conceptions of structural definition both in the history of modern axiomatics and in contemporary philosophical debates. Based on that, we give a systematic assessment of the underlying semantics of these two ways of understanding the definiens of such definitions, by considering alternative model-theoretic and inferential accounts of meaning.

Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations

The three subtypes (α, β, and γ) of the retinoic acid receptor (RAR) are ligand-dependent transcription factors that mediate retinoic acid signaling by forming heterodimers with the retinoid X receptor (RXR). Heterodimers are functional units that bind ligands (retinoids), transcriptional co-regulators and DNA, to regulate gene networks controlling cell growth, differentiation, and death. Using biochemical, crystallographic, and cellular approaches, we have set out to explore the spectrum of possibilities to regulate RXR-RAR heterodimer-dependent transcription through various pharmacological classes of RAR- and RXR- specific ligands, alone or in combination. We reveal the molecular details by which these compounds direct specificity and functionality of RXR-RAR heterodimers. Among these ligands, we have reevaluated and improved the molecular and structural definition of compounds CD2665, Ro41-5253, LE135, or LG100754, highlighting novel functional features of these molecules. Our analysis reveals a model of RXR-RAR heterodimer action in which each subunit retains its intrinsic properties in terms of ligand and co-regulator binding. However, their interplay upon the combined action of RAR- and RXR-ligands allows for the fine tuning of heterodimer activity. It also stresses the importance of accurate ligand characterization to use synthetic selective retinoids appropriately and avoid data misinterpretations.